Various publications, including patents, published applications, technical articles and scholarly articles are cited throughout the specification. Each of these cited publications is incorporated by reference herein, in its entirety and for all purposes.
The poly ADP-ribose (ADPr) polymerase, PARP-1, is an essential protein involved in a wide range of cellular functions, including genotoxic stress response, transcription activation, cellular differentiation, DNA-repair, among others. On the molecular level, PARP-1 binds to DNA and catalyzes the transfer of ADPr and de novo synthesis of poly ADPr by utilizing the glycolytic intermediate nicotinamide adenine dinucleotide (NAD+) as a substrate. PARP-1 modifies itself and modifies its target proteins by adding ADPr to glutamic residues. The addition of ADPr polymers regulates the catalytic and DNA binding activity of PARP1 as well as the cellular activity and localization of its target proteins.
It was previously determined that PARP-1 enzymatic activity is required for normal assembly of higher-order chromatin structures as well as for the transcriptional activation of heat-shock-dependent, NF-kB-dependent, ecdysteroid-dependent, and ribosomal genes. These studies demonstrated that PARP-1 regulates the transcription of these genes by inducing chromatin loosening at targeted genetic loci. These roles are distinct from the previously characterized roles of PARP-1 in DNA repair and apoptosis.
PARP-1 inhibitors have been shown to selectively eliminate several types of tumorigenic cells. In recent years, PARP-1 inhibitors became popular in clinical research on novel strategies of cancer treatment and, a number of PARP-1 inhibitors are currently undergoing clinical trials for treatment of genetically disposed mutant tumors. Unfortunately, a number of clinical studies reported setbacks in research on PARP-1-based anticancer therapies.
One of the factors that may limit the potency of PARP-1 inhibitors is the majority of currently available inhibitors were designed as NAD competitors. NAD is abundant, ubiquitous, and is used by many other enzymes. Therefore, it is very difficult to completely eliminate NAD interaction with PARP-1 without drastically affecting other metabolic processes. Moreover, as classical PARP-1 inhibitors demonstrate substantial similarities to nucleotide analogues, they obstruct functions of enzymes which utilizing nucleotides as cofactors, such as kinases.
As PARP-1 remains a viable target in cancer therapy, there remains a need for PARP-1 inhibitors that do not affect other enzymes or other normal metabolic processes. Relatedly, there remains a need for PARP-1 inhibitors that diverge from the established model of aiming at the NAD-PARP-1 interaction.